A number of human and animal conditions are associated with inflammation. To date, very few reliable or effective therapies exist for these conditions. However, the terrible symptoms associated with these conditions may be substantially reduced by employing therapies that decrease inflammation in patients suffering from the condition. While not curing the conditions, such therapies would significantly improve the quality of life for these patients and could ameliorate some of the effects of these conditions. Thus, there is a need in the art to identify new therapies that may contribute to an overall decrease in inflammation in patients suffering from these conditions.
Inflammatory conditions are often associated with inappropriate regulation of cytokines (Han et al., Nature Cell Biol., E39-E40 (1999)). For this reason, the selective inhibitors of inflammatory cytokine expression are potential agents for the treatment of conditions related to inflammation.
MAPKAP kinase 2 (MK2) is thought to contribute to the regulation of several cytokines and thus may be an essential component of the inflammatory response. Mice with a null mutation for MK2 show an increased resistance to lipopolysaccharide-induced endotoxic shock (Kotlyrov et al., Nature Cell Biol., 1:94-97 (1999)). This stress resistance is thought to result from the decrease in the biosynthesis of several inflammatory cytokines including TNF-α, IL-1β, IL-6, IL-10, and IFN-γ. Because of the role of MK2 in the regulation of inflammatory cytokines, proteins that bind and inhibit MK2 activity are potential agents for decreasing inflammation.
MK2 has been shown to associate with a number of proteins. MK2 is phosphorylated by p38 MAP kinase in response to certain environmental stress or inflammatory cytokines (Kotlyarov et al., Nature Cell Biology, 1:94-97 (1999)), as shown in FIG. 7. MK2 phosphorylates serum response factor (SRF) (Heidenreich et al., J. Biol. Chem., 274:14434-14443 (1999)), CREB and ER81 (Janknecht, J. Biol. Chem., 276:41856-41861 (2001)), small heat shock protein and leukocyte specific protein 1 (reviewed in Neininger et al., EMBO Reports, 2:703-708 (2001)), E47 (Neufeld et al., J. Biol. Chem., 275:20239-20242 (2000)), Akt (Rane et al., J. Biol. Chem., 276:3517-3523 (2001)), tyrosine hydroxylase, and TTP (Mahtani et al., Mol. Cell Biol., 21:6461-6469 (2001)). In addition, MK2 interacts with 5-lipoxygenase, which catalyzes important steps in the synthesis of leukotrienes, which are a group of inflammatory mediators (Janknecht, J. Biol. Chem. 276:41856-41861 (2001)). One protein hnRNP A0, however, has been shown to be differentially regulated in MK2+/+ and −/− cells.
Thus, due to MK2's involvement in inflammatory responses, it may be a desirable target for therapeutic intervention. In particular, therapeutic agents that inhibit the activity of MK2 may be used to treat human or animal conditions in which a decrease in inflammation would be therapeutically beneficial.